Treatment evaluation of combined modality therapy: ‘What can we obtain today from Phase II trials?’

ELSEVIER SCIENCE IRELAND

Lung Cancer 10 Suppl. 10994) S117-S133

Treatment evaluation of combined modality therapy: ‘What can we obtain today from Phase II trials?’ N. Thatcher Christie Hospital, CRC Department of Medical Oncology, Wilmslow Road, Manchester M.20 9BX, UK

Abstract Demonstration of activity is the major goal of Phase II studies. Other end points-duration of response, survival (relapse free in complete responders), progression free interval, changes in performance status and quality of life also provide useful information. From these data a decision to continue or discard a particular therapy can be considered. Various handicaps including variability in response reporting, heterogeneity of patient populations, inadequate reporting of failure patterns, causes of death, performance status changes and quality of life hinder interpretation of Phase II data. Nevertheless, Phase II studies have defined prognostic groups, beneficial changes in performance status and have helped formulate novel management approaches. Targeting particular prognostic groups, investigat-

ing dose-intensive regimens with haemopoietic growth-factor support and novel combinedmodality approaches have all been generated through Phase II investigations. Key words: Reporting variability; Prognostic factors; Novel therapy

The decision as to whether a new drug or therapeutic approach, e.g. combined modality therapy is of sufficient efficacy to warrant further large scale study is based on Phase II testing. The hallmarks of reliable Phase II studies are quality control and reproducibility.

1. Variability in reporting

Regrettably we have learnt that particular problems exist in Phase II investigations [18,23,58,60,67,72]. Perhaps the greatest is the variability in the reporting of 0169-5002/94/$07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved. SSDI 0169-5002(93)00272-B

N. Thatcher/ Lung Cancer 10 Suppl. I (1994) Sll7-S133

S118 Table 1 Single agent response in NSCLC

Dw

Range of overall response rate (%)

Mean overall response rate OR (%)

Ifosfamide Cisplatin Mitomycin Vindesine

7-32 6-32 9-40 6-31

26 20 20 17

Doxorubicin Etoposide Methotrexate Cyclophosphamide

6-38 3-21 O-26 4-42

13 11 10 8

Modified from Bakowski and Crouch [7].

tumour response rates as exemplified for non-small cell lung cancer (NSCLC) [7] (Table 1). Nevertheless by identifying this discrepancy in reporting, attention has been directed to the problem and possible remedies suggested (Table 2). Realisation of the non-homogeneity of patient groups was illustrated by the stark effect of previous treatment, versus no prior chemotherapy for etoposide (10% vs. 40%) and carboplatin (19% vs. 60%) response rates in small cell lung cancer (SCLC) patients [18]. Inferior results in previously untreated patients with extensive stage SCLC were obtained also with a new drug idarubicin despite switching promptly in non-responders to cyclophosphamide, vincristine and etoposide. This type of Phase II information led to guidelines, for study design and result reporting of new agents in previously untreated SCLC patients [14,18]. Another approach is to reduce the

Table 2 Phase II studies: problems identified/remedied Variability in reporting treatment effects. Patient groups non-homogenous Criteria different, assessments different and difficult Failure patterns, causes of death Reporting of events - ‘quality of life’, treatment actually given inadequate Treatment centre, team Identification of ‘active’ therapy Prognostic groups Value of ‘response’ Changes in performance status, quality of life Analyses (spin offs) of Phase II studies Suggestion for novel management approaches Use of prognostic factors Toxicity factors Dose intensity, haemopoeitic growth factors

N. Thatcher/ Lung Cancer 10 Suppl. 1 (1994) Sll7-S133

Sll’)

‘active’ response rate to 2 10% in previously treated patients. Such a design would also help identify non-cross resistant agents [33]. An important cause for the variability in response rates and survival are clearly differences in the characteristics of patients entering different studies. The consensus report for NSCLC indicates that performance status and stage/extent of disease were of definite importance whereas weight loss, sex, lactate dehydrogenase were all possible factors [26]. The problem can be further exemplified by a study from the Brussels group who performed an overall analysis of chemotherapy reports during the past 15 years in advanced NSCLC. It was found that in less than half the articles reviewed, the response rate was related to the important prognostic factor of disease extent [23]. Variability in the outcome parameters also arise when different criteria and assessment techniques are employed for reporting. In a review of 61 reports of chemotherapy trials no article contained all the information required to define precisely the criteria for tumour response in NSCLC [67]. Demonstration of activity, i.e. tumour response is the major goal of a Phase II trial. This implies that response can only be objectively assessed in patients in whom the tumours are measurable in two dimensions or at least evaluable in one. Complete response requires the disappearance of all evidence of disease and no new appearance of disease for at least 4 weeks. Partial response requires reduction by at least 50% of all lesions for 4 weeks with no new appearance of disease. Progression indicates tumour growth whilst receiving treatment with increases in lesions by at least 25% or the appearance of new tumour. The start and end of response, minimum number of assessments for response determination and the duration of response often taken from the start of therapy until demonstration of progression should be routinely given [58]. Fixed times, land-marks after start of treatment should be identified when conducting analyses. This can be 3-4 weeks after induction therapy. In this manner initial response to chemotherapy can be determined particularly in patients for whom combined modality therapy is being contemplated, it helps define the optimal number of chemotherapy cycles and avoids the toxicity of unnecessary cycles [58]. Other parameters of interest in Phase II studies include symptomatic response although objective response can be a possible surrogate for this index of activity and toxicity. The adoption of standard criteria, e.g. WHO ECOG, EORTC in evaluation of response is now routine and should be mandatory for reporting Phase II studies. By using the standard criteria much of the variability in previous reporting of Phase II trials can be removed [58]. Another area of variability occurs in the assessment of different indicator lesions: metastatic lung nodules are much more reliable than hepatic lesions and indeed false categorisation of response was recorded in 18% of cases when several physicians were asked to evaluate the parameter [72]. Another major problem which hinders our understanding of the disease has been the inconsistency in how failure patterns are reported [40]. This is of importance when treatments have different effectiveness. A less effective treatment could permit the earlier identification of distant metastases before local recurrence became obvious. A more effective treatment would be expected to delay

s120

N. Thatcher/Lung

Cancer 10 Suppl. I (1994) S117-S133

the onset and identification of distant deposits with apparent sole failure occurring at the primary site [40]. Further difficulties exist in defining recurrence within an irradiated field, at its margin or indeed outside the chest field, and the apparent failure pattern may be influenced by the use of different restaging methods. Another methodological issue concerns the time point at which relapse is recorded. Actuarial reporting of freedom from recurrence has been encouraged rather than the use of frequency analysis. This issue has been addressed in a recent communication which examined 202 patients with limited stage SCLC in four consecutive Phase II studies of alternating radiotherapy and chemotherapy. It was noted that the first cause of failure was local only in 33%, distant only in 25%, both patterns simultaneously in 9% with an 8% intercurrent death rate. Methodology of competing risks allowed the identification of first events [4]. It is also important to record the proportion of patients entered into a study compared with those not entered but eligible with the same prognostic characteristics: another area for possible selection bias particularly in multicentre studies when unusually small patient numbers are entered by one institution. The causes of death and toxicity after the 2-year follow-up point are also under reported. Two recent SCLC abstracts indicate the importance of second solid tumours in causing death [52,68]. Chronic toxicity problems particularly with combined modality treatment, e.g. radiation pulmonary fibrosis and neuropsychiatric problems may also be understated due to lack of long-term follow up reports. A major problem in lung cancer is accruing quality of life data and the poor compliance, indeed worth while results may not be obtained despite good protocol design [15,38]. In the future changes in performance status and quality of life should be reported using standard instruments, e.g. the Hospital Anxiety Depression Score and Rotterdam Symptom Check List. Another issue which has until recently been almost entirely overlooked has been the variation from the planned protocol treatment. Dose intensity in solid tumour treatment is now the subject of considerable interest [22]. A standard calculation is desirable and certainly reporting the actual treatment given rather than that intended is clearly essential. It is therefore recommended that the proportion of planned dose actually delivered and the magnitude of delay for each modality of treatment should be stated. Treating dose intensity as a characteristic of a particular patient’s entire treatment course is preferable to describing dose intensity for a particular cycle of treatment within the population receiving the cycle. By using the former methodology the actual dose intensity is more accurately reflected by capturing the duration of the actual treatment course. Thereby dose intensity can be investigated as a prognostic factor in future studies [45]. Variation in treatment from that intended also can be due to the individual physicians’ perceptions and the physicians’ tolerance to toxicity rather than that of the patient. In a study of combined chemotherapy and radiotherapy in SCLC, the dose received, even with the first course of chemotherapy, was quite variable. The importance of the variation was illustrated by the finding that the intensity of the first course was an important prognostic factor [21]. From earlier Phase II reports it was recognised than many did not provide adequate information to allow evaluation of new treatments. Appropriate record-

N. Thatcher/Lung Cancer 10 Suppl. 1 (1994) S117-S133

s121

ing of patient characteristics is probably the most important aspect of the problem. Difficulties exist in defining regponse and duration particularly in patients receiving combined modality therapy. Marker lesions in lung cancer are often not conveniently bi-dimensionally measurable in advanced disease. Differences between partial and complete remission can be difficult to define and lung atelectasis adds a particular problem for assessment in lung cancer. Therefore despite good design, the final reporting may not permit sensible comparison between studies. Rigorous standards must therefore be insisted upon and now, to a large extent, are defined. More adequate reporting of events, not only response and survival but also toxicity, performance status, quality of life and causes of death, should be encouraged. 2. Identification of active therapy Phase II studies also can provide additional information on treatment activity by taking into account prognostic factors. In one of the larger multivariate Cox analyses based on over 2000 patients in SWOG studies in extensive NSCLC, good performance status, female sex and cisplatin based regiments were all associated with improved survival independent of other prognostic factors 111.It has also been claimed that patients with tumours that undergo a slower response tend to survive longer and histology could be important in defining a subgroup of advanced tumours more likely to respond to chemotherapy. Part of the solution may lie in identifying those NSCLC tumours which exhibit neuro endocrine features [26,46]. The identification of prognostic factors in SCLC has received considerable attention. Phase II studies from single institutions have identified a number of factors by multivariate analysis. For example in Manchester lactate dehydrogenase, stage, sodium, performance status alkaline phosphatase and bicarbonate (out of 61 pre-treatment variables) were found to be of independant significance [161. The latter parameter probably reflects the large number of patients on diuretics with co-existant non-malignant cardiorespiratory disease. By amalgamating data sets from several institutions Rawson and Peto confirmed the importance of performance status, stage and biochemical assessment [51]. Indeed the necessity for expensive, time consuming and elaborate investigations, e.g. CT scans, bone marrow trephines, began to be questioned in the routine investigation of SCLC [16,47,51,69]. Recognising the prognostic factors that influence the results of Phase II studies allows the clinician to target defined patient populations with appropriate incorporation into the design and analysis of future studies. Cross comparison between studies should then be more informative and heterogeneity in the patient populations allowed for when interpreting results. A major criticism has been that differences in the observed response rate may just represent inherent differences in patient characteristics under study rather than the true difference in the activity of treatment The question of the value of response as a prognostic criterium in NSCLC has been addressed by Sorenson [58]. Pre-treatment variables which provide information on survival may not necessarily be identical to those predicting response and toxicity. Furthermore patients with a prolonged survival will be on study for a longer period of time that those dying

s122

h? Thatcher/Lung Cancer 10 Suppl. I (1994) S117-S133

Table 3 Change in ‘performance status’ in metastatic NSCLC Reference

Regimen

Patient Nos.

OR (%)

Survival median (months)

Performance status % of patients Better

Stable

Worse

Bakker [8]

PVaB

28

48

8

1 patient

Thatcher [62]

I

48

29

5

37

35

28

Thatcher [66]

IC

45

38

7

40

27

33

Cullen [ 191

MIP

76

56

9

30

61

Evans [25]

BSC CAP

53 100 98

15 25

vDp

17 weeks 25 weeks 33 weeks

4 12 7

Hardy [36]

MVaP

24

21

6

67

12

21

Kris [44]

EDAM MV,

85

59

12.8

44

40

26

Gurney [35]

IM

42

24

7

24

64

12

von Rohr [70]

MI Carbo

34

32

10 +

37

30

33

I, ifosfamide; P, cisplatin; V,, vinblastine; B, bleomycin; C, cyclophosphamide; M, mitomycin C; BSC, best supportive care; CAP, cyclophosphamide, doxorubicin, cisplatin. V,P, vindesine, cisplatin; EDAM, edatrexate; Carbo, carboplatin

earlier and may have inherently a better chance of achieving chemotherapy response. The importance of performance status in prognostic scoring has been recognised but as a measure of treatment efficacy largely has been ignored. In NSCLC studies, where adequate data are available, the performance status improved in about one-third of patients and in another one-third stabilised (Table 3). These Phase II data do argue against the general perception that all patients who receive advanced NSCLC deteriorate with treatment chemotherapy for [8,19,25,35,36,44,62,66,70]. If two treatments give the same survival, then differences in toxicity, change in performance status or quality of life between the two groups can determine a treatment advantage. Indeed in one study a 48% response rate was described with a cisplatin combination in NSCLC but the fall in performance status removed any potential benefit for the majority of patients despite the high response rate [8]. When considering SCLC therapy it is also important to identify a fast symptomatic response to treatment given this tumour’s natural history. Reporting changes in the performance score and a major symptom such as breathlessness help describe the patients ‘well being’ in addition to the standard reporting of acute treatment toxicity. These data are of interest when intensive toxic combined modality regimens are used in patients with SCLC (Table 4) [48,65].

s123

N. Thatcher/ Lung Cancer 10 Suppl. 1 (1994) Sll7-S133

Table 4 Change in Karnofsky performance (KP) score and respiratory assessment score (RA) with intensive combined modality therapy in SCLC Pre-treatment

score after CT course

Post-treatment

2

4

(5%)

(o/o)

(96)

(o/C)

10 73 17

2 23 70

2 23 63

12 8 80

5

12

85 8 2

88

5

12

KP Score

< 50 50-70 SO-100 Pts. who did not complete treatment RA Score 192 3.4 5 Pts. who did not complete treatment

23 60 17

-

85 2 13

RA score 1 and 2; climbs hills, stairs, walk any distance on the flat at normal pace, without dyspnoea; Grades 3 and 4: walks more than 100 yards at own speed without dyspnoea, dyspnoea walking 100 yards or less. Grade 5: dyspnoea on mild exertion, e.g. undressing. Prendiville et al. [48] with permission.

3. Phase II study analyses The experience derived from earlier Phase II studies, and the identification of prognostic factors have allowed more rational targeting of patients more likely to benefit from chemotherapy. 3.1. Non-small cell lung cancer It was logical to use preoperative or neoadjuvant chemotherapy followed by surgery in patients with Stage IIIA/B disease. Chemotherapy regimens were selected from earlier Phase II studies and all involved cisplatin, an extensive review of chemotherapy trials in advanced NSCLC over the past 15 years has been reported recently [23]. Response rates were found to be significantly lower with single agent chemotherapy than for combination chemotherapy and best results were obtained with regimens employing cisplatin, vindesine, vinblastine, mitomycin C and ifosfamide. It was also suggested that a higher dose of cisplatin (100 mg/m’ rather than 70 mg/m2) was associated with better responses particularly in limited disease [23]. Such data are of importance in helping design neoadjuvant trials in patients with NSCLC. A number of Phase II studies have reported on neoadjuvant chemotherapy, some with radiotherapy followed by surgery. Investigations on 40 patients or more

S124

N.

Thatcher/Lung

Cancer 10 Suppl. I (1994) S117-S133

Table 5 Neoadjuvant chemotherapy in locally advanced NSCLC (studies of more than 40 patients) Reference

Regimen

RT

Number of Patients.

OR%

Complete Resection %

Median Survival (months)

Taylor [61]

5 FUP

+

64

56

60

15

Gralla [30]

MVP VP

-

58

62

51

19.5

Weiden [73]

5NP

+

53

57

42

10.5

Skarin [55]

CAP

+

41

53

85

32

Henriquez [37]

MVP

f

53

68

49

15 +

Weitberg [74]

PE

+

44

71

48

16

Gralla [31]

MVP

-

73

78

60

19

Ravasi [50]

Pci

+

41

84

51

35% at 2 years

5FU, 5 fluorouracil; P, cisplatin; M, mitomycin C; V, vinca alkaloid; RT, radiotherapy; ci, continuous infusion.

are shown in Table 5. These Phase II studies indicate that patients treated with stage IIIA/B disease have objective response rates higher than those usually seen using the same chemotherapy in more advanced patients. Of considerable interest is the possibility of complete resection, and a recent overview indicates that 46% of patients can be resected [43]. From these Phase II studies other important information has been obtained. Resected samples regularly showed tumour necrosis and no viable tumour has been found in 7-27% of the resected samples [13]. Histological response has also been found to be a significant prognostic factor [32]. Furthermore some patients who have been designated as having a clinical partial response have on examination of the operative specimens been shown to have no tumour. A number of questions remain, however, which could be addressed in further Phase II studies, best chemotherapy regimen, how long should it be given before surgery and the scheduling of any surgery and radiotherapy. Whether the approach of preoperative chemotherapy will improve survival given the selected nature of the population remains to be proven in randomised studies. However, the Phase II work does suggest the survival from the neoadjuvant studies appears historically better than those obtained with radiotherapy alone [31]. The rationale for combined radiotherapy and chemotherapy in inoperable NSCLC has been summarised with the prospect of radiosensitisation by certain drugs when given in close association with the radiation. Inadequacy of detail in many of the reports, difficulty in assessment of endpoints such as locoregional thoracic tumour control, pattern of metastatic spread, time to recurrence and

N. Thatcher/Lung Cancer 10 Suppi. 1 (1994) Sll7-S133

S125

quality of life, etc. were highlighted [ll]. Nevertheless it has been emphasised that major disease regression can occur in up to 75% of previously untreated patients given combined modality therapy [34]. Phase II studies have demonstrated the feasibility of giving full dose thoracic radiotherapy after induction chemotherapy without undue side effects but there is still the need to improve local control in Stage III disease [34]. One approach to improve the efficacy of chemotherapy is to give continuous infusions with concurrent radiotherapy. The advantage of combined modality therapy particularly when cisplatin is used either concurrently or in close proximity to the radiotherapy perhaps acting as a radiosensitizer has been expressed [13,43]. For example platinum is possibly more effective when given over several days rather than on a weekly schedule [53]. Another approach which improves the feasibility of this type of therapy is to use continuous infusion platinum in ambulatory pumps. Cisplatin is stable for over a week in plastic reservoirs [39]. This technique is already being tested in patients with advanced NSCLC allowing an outpatient-based treatment, little toxicity with an objective response rate of 39% in Stage IIIB/IV disease [lo]. A similar technique using a portable pump system and cisplatin continuous infusions concurrently with radiotherapy in stage IIIA/B disease produced a 35% survival probability (23% progression free) at 2 years [50]. Another approach is to give the modalities in a closely spaced alternating fashion, allowing high-dose intensity without the normal tissue toxicity seen with concurrent treatment. In patients with stage IIIA/IIIB disease thoracic irradiation was given twice per day 5 days/week alternating with cisplatin and etoposide, with an overall response rate of 58%, and a median survival of 12.5 months. Interestingly residual inter-thoracic mass at end of treatment did not relate to subsequent disease progression in the chest [71]. Other preliminary reports of alternating chemotherapy and radiotherapy in stage IIIA/IIIB disease have suggested that radiotherapy improves the quality of response following chemotherapy [9]. Alternating radiotherapy even with high-dose cisplatin (100 mg/m*) is feasible and has resulted in a median survival of 25 months [28]. The Marburg group extended the combined modality notion by giving either radiotherapy plus cisplatin as a radiosensitizer or chemotherapy, ifosfamide, vindesine followed by radiotherapy and cisplatin. The incidence of distant metastases as first site of relapse was not decreased but median survivals of 13.5 months compared with 10.7 months and the 2-year survivals of 27% compared with 16% were in favour of combination chemotherapy being given before radiotherapy and cisplatin [75]. 3.2. Small cell lung cancer The definition of prognostic factors in SCLC allows scoring of the individual based on adverse factors. It now seems reasonable to include some patients with extensive stage disease into a better prognosis group providing such patients have a good performance status and normal biochemistry [16]. With such a scoring system and current therapeutic inadequacy it is not sensible to treat all patients in the same way. Treatment can be targeted in a more rational manner to particular patient groups.

S126

N. Thatcher/ Lung Cancer IO Suppl. 1 (1994) SlI 7-S133

3.2.1. Poor prognostic groups As an example novel management approaches with conventional agents have been adopted for the poorer prognostic groups using variations on the ifosfamide, etoposide regimen shown to be effective in previous Phase II studies 1631. Bolus ifosfamide and mesna over 30 min with oral etoposide over 8 days were given on an outpatient basis to poor risk patients who were elderly with poor performance status and biochemical abnormalities [2] (Table 6). Importantly, a rapid improvement in the patient’s Karnofsky performance status occurred soon after starting treatment [2]. In another variation oral ifosfamide, which is known to have a fast absorption and high bioavailability, was given over 3 days with oral etoposide [17]. The results, particularly the 2-year survival in patients with adverse prognostic factors suggested further exploration of this method of administration (Table 6). Pump infusion chemotherapy has already been mentioned in the context of NSCLC but a number of drugs effective in SCLC are also known to be stable in the plastic pump reservoirs. The continuous ambulatory infusions allow treatment to be given over just 6 weeks, the reservoir being recharged with either doxorubicin or ifosfamide mesna every 7 days. Pump infusion appears to be less toxic, associated with a higher complete response rate and with fewer treatment delays compared with conventional bolus type of administration [3]. The concept of short-duration chemotherapy in this case over just 6 weeks is of importance in the poorer prognosis patients. Thoracic radiotherapy can also be administered in association with these novel treatment approaches without additional toxicity. Investigation of Phase II studies addressing treatment of older SCLC patients (those of 70 years or more) concluded that elderly patients were less able to tolerate chemotherapy but survival of patients who completed four or more cycles was similar to that of younger patients of equivalent stages [54]. Generally oral etoposide is considered to be a convenient and ‘easy’ treatment for poorer prognosis patients, but at a dose of 50 mg bd for 14 days or 21 days was associated with poor tolerability and poor palliation [24,56]. Valuable lessons have then have been learnt from examination of Phase II studies in defined populations. 3.2.2 Better prognostic groups The problem identified in previous Phase II studies of thoracic and cerebral relapse following chemotherapy alone in SCLC led to combined modality treatment with radiotherapy and chemotherapy. For the better prognostic groups a variety of Phase II studies employing the ICE (ifosfamide, carboplatin, etoposide) type regimen have been undertaken by the Manchester group (Tables 6 and 7). The regimen was based on Phase II observations of ifosfamide, etoposide and the high single agent activity of carboplatin (Table 6) [64]. The ICE studies have been associated with 2-year actual survivals of 30% or more and have indeed included patients with extensive stage disease but no other adverse prognostic features. Furthermore, in the Manchester studies patients are not intensively staged with CT scans. In the first study of ICE with mid-course vincristine, treatment was given over six courses at 4-week intervals with thoracic irradiation at the end of chemotherapy but no PCI. Subsequent studies, the latest as yet not reported in full, has used PC1 within 1 week after the first course of chemotherapy and thoracic

S127

N. Thatcher/ Lung Cancer 10 Suppl. 1 (1994) SlI 7-S133

Table 6 Ifosfamide with mesna (I) and etoposide (El in SCLC Reference

No. of patients

Thatcher [63]

78 LS 90 76 85 ES 65 27 I, 5 g/m2 i.v. dl; E, 120 mg/m’ i.v. d1,2; 240 mg/m* 20 LS 75 35 27 ES 48 11 I, 1.5 g/m* i.v. dl; E, 100 mg orally dl-8 25 LS 80 48 40 ES 85 17 I, 2 g dl-3 orally; E, 100 mg orally dl-8

Anderson [2]

Cerny [171

Stage

OR (o/o)

CR (%)

Median survival (months)

Survival (%l 2 years

11 8 orally d3 8 5.5

22” 5a

13 9.5

22” 6a

11” 4a

LS, limited stage; ES, extensive stage. aActuaI survival.

radiotherapy within 1 week after the third course of chemotherapy. The radiotherapy has been given as a single fraction 8 Gy for PC1 and 12.5 Gy when possible as thoracic irradiation. Two other aspects of these intensive Phase II studies are of importance, no dose reductions are performed although delays are allowed for recovery but despite the intensity of the severe myelosuppression and subsequent support needed the performance status improved rapidly with treatment (Table 4). The majority of patients are also able to receive all six courses of treatment with the scheduled radiotherapy [48,65]. Combined modality treatment in limited stage SCLC has been the subject of other novel investigations using concurrent hyperfractionated radiotherapy reported mainly from the United States of America and interdigitated alternating regimens of chemotherapy and radiotherapy of the French group. A summary of these novel treatment programmes is given in Table 8. The American groups attempt to maximise tumour kill with normal cell sparing by giving radiotherapy to the chest in two daily doses 4-6 h apart with concurrent cisplatin and etoposide followed by further chemotherapy. The alternating regimens were designed to give radiotherapy early without delaying chemotherapy and avoiding the complications associated with concurrent administration particularly of doxorubicin and radiotherapy. It should be noted that in all these studies the numbers of patients accrued yearly are relatively small suggesting considerable selectivity. The death rate unrelated to cancer and possibly due to treatment-related causes in these studies is about 5% although this can rise in association with the higher chemotherapy doses [5,6,12]. Nevertheless these new approaches of combined modality therapy have produced some of the best survival figures so far, albeit in selected populations, and need to be investigated further through randomised Phase III trials. Other advantages arising from Phase II studies include toxicity information. The pattern of myelosuppression suggested a study model for examining haemopoietic

N. Thatcher/Lung Cancer IOSuppl. 1 (1994) S117-S133

S128

Table 7 Three and four drug combinations including ifosfamide (I), carboplatin (C), etoposide (El regimens in SCLC

Reference

Patient number

Gatzemeier 1991 i291

63 58

Stage

LS ES

XRT

TI/PCI

OR%

84 81

CR%

52 33

Median survival (months)

Survival

13.0 9.0

52% 31%

l-year

2-year

3-year 29% 9%

C-300 mg/m’ dl E-140 mg/m’ i.v. dl-3; V-l.4 mg/m2 d1,8,15

Thatcher 1989 I651

29 12

LS ES

TI

79 83

55 67

14 14

33%* 25%*

C-300 mg/m2 dl, E-120 mg iv. d1,2 240 mg/m2 orally d3; I-5 g/m2 dl V-O.5 mg/m2 d14

Smith 1990 I571

18 14

LS ES

TI/PCI

94 100

72 29

C-400 mg/m2 dl, E-100 mg/m2 iv. dl-3

Prendiville 1991 [481

31 9

LS ES

TI/PCI

84 78

74 56

19 9.5

24% 14%

I-5 mg/m2 iv. dl

15 9

32%* 22%*

Cisplatin 100 mg/m’ dl alternating with C-300 mg/m2 E-120 mg/m2 i.v. d1,2 and 240 mg/m* orally d3; I-5 g/m2 dl; V-l mg/m2 d14

Thatcher 1992 (in preparation)

73 14

LS ES

TI/PCI

84 77

61 31

16.6 13.4

32* 21*

As for Thatcher 1989 but with PC1 and TI V, vincristine; TI, thoracic irradiation; *Actual survival.

colony stimulating factors. The ICE regimen which is associated with good 2-year survival rates is now the subject of a series of randomised studies involving G-CSF, GM-CSF and erythropoietin. The latter has already shown to reduce the need for blood transfusions and to have a favourable influence on platelet transfusion requirements [20]. Another advantage of the Phase II study organisation is the collection of data which allow further analysis of interesting topics. In the Manchester studies full protocol doses were employed throughout with no dose reduction after episodes of severe or life threatening sepsis. It has therefore been possible to

N. Thatcher/Lung

Table 8 Alternating radiotherapy and chemotherapy

Protocol References

002 protocol 1980-1981161

004 protocol 1982-1984 [6] 006 protocol 198551986 [6] MRC Bleehen [12]

S129

Cancer 10 Suppl. 1 (1994) S117-S133

Patient Nos.

28

in limited stage SCLC

CT/T1

OR(%)

CAEM

CR(%)

Median survival (months)

17.2

27% (DFS)

21% (DFS)

23 (DFS) 31%

;:FS) NS

NS

64

CAEP

NS

69%

NS

22

CAEP

77%

64%

11

34 36

Souquet [59] Frytak [27]

89 27

Arriagada [5]

29

Survival

79% CAEP

Johnson [42] Johnson [41]

3 years

NS

81

Hyperfractionated

2 years

radiotherapy and chemotherapy limited stage SCLC

PE/bd PE-CAV or individualised/bd AVI/bd P infusion CE/bd DECP/tds 1st course then daily fractions as previously

97 100

59 78

17.8 27

50 65

37 NS

63 NS

47 NS

14 22

NS NS

NS NS

NS

76

NS

NS

:;FSl

Protocols 002,004 and 006 modified from Arriagada [6]. P, cisplatin; E, etoposide; C, cyclophosphamide; A, doxorubicin; V, vincristine; M, methotrexate; DFS, disease free survival; NS, not stated; TI, thoracic irradiation.

determine the incidence of sepsis or death from sepsis in 382 patients treated in a single centre with combined modality treatment. A total of 50 patients (13%) had 66 episodes of severe life threatening sepsis associated with 1978 cycles of chemotherapy, i.e. only 3% of cycles were affected. Twenty deaths due to sepsis occurred of whom only four occurred in patients who has previously experienced a septic episode earlier in their treatment. The others died as a result of the first septic episode. These data could argue against the general principle of dose reduction to prevent sepsis and indeed a model has been constructed to determine the population at high risk of sepsis [491. Appropriate decisions can then be made about the type and intensity of chemotherapy depending on risk factors. 4. Conclusion A series of novel management approaches in lung cancer have arisen from earlier Phase II studies. The methodology leads the way in suggesting new concepts

s130

N. Thatcher/Lung Cancer IO Suppl. 1 (1994) SIl7-S133

of treatment. These include targeting of patients with dose-intensive programmes with haemopoietic growth-factor support and methods of applying combined modality treatment to improve the management of lung cancer patients in the future. 5. References 1 Albain K, Crowley J, LeBlanc M, et al. Does ciplatin (DDPl-based therapy improve survival in extensive non-small cell lung cancer (NSCLC)? Southwest Oncology Group (SWOG) Studies. Proc Am Sot Clin Oncol 1990; 9 (Abstract 877): 227. 2 Anderson H, Lind MJ, Thatcher N, et al. Therapy for poor-risk patients with small cell lung cancer using bolus ifofamide and oral etoposide. Cancer Chemother Pharmacol 1990; 26: 71-4. 3 Anderson H, Prendiville J, Thatcher N. A randomized study of intravenous bolus versus continuous infusion of ifosfamide and adriamycin with oral etoposide for small cell lung cancer. Cancer Res Clin Oncol 1990; 116 (Abstract 05:05:03): 819. 4 Arriagada R, Kramar A, Le Chevalier T, et al. The competing risk approach in determining relapse-free survival in limited small cell lung carcinoma. Lung Cancer 1991; 7 (Suppl Abstract 347): 95. 5 Arriagada R, Pellae-Cosset B, Baldeyrou P, et al. Initial high dose chemotherapy (CT) and multifractionated (MDF) radiotherapy (RT) in limited small cell lung cancer (SCLC). Lung Cancer 1991; 7 (Suppl Abstact 591): 159. 6 Arriagada R, Pignon JP, Le. Chevalier T. Thoracic radiotherapy in small cell lung cancer: rationale for timing and fractionation. Lung Cancer 1989; 5: 237-47. 7 Bakowski M, Crouch JC. Chemotherapy of non-small cell lung cancer: a reappraisal and a look to the future. Cancer Treat Rev 1983; 10: 159-72. 8 Bakker W, Van Oosterom AT, Aaronson NK, et al. Vindesine, cisplatin and bleomycin combination chemotherapy in non-small cell lung cancer: survival and quality of life. Eur J Cancer Clin Oncol 1986; 22: 963-70. 9 Bardella D, Fiorentini G, Solaini L, et al. Alternating neoadjuvant chemotherapy (ANCH) and radiotherapy (RT) in advanced non-small cell lung cancer (NSCLC). Lung Cancer 1991; 7 (Suppl Abstract 581): 156. 10 Bedini AV, Tavecchio A, Gramaglia A, Alloisio M, Ravasi G. Alternating sequential cisplatin (CDDP) and 5-fluorouracil (FU) in continuous infusion (CD for advanced bronchogenic carcinoma. Lung Cancer 1991; 7 (Suppl Abstract 525): 140. 11 Bleehen NM. Combined radiotherapy with chemotherapy for inoperable non-small cell lung cancer. Lung Cancer 1991; 7: 85-9. 12 Bleehen NM, Girling DJ, Gregor A, et al. A Medical Research Council Phase II trial of alternating chemotherapy and radiotherapy in small cell lung cancer. Br J Cancer 1991; 64: 775-9. 13 Bunn PA. The expanding role of cisplatin in the treatment of non-small cell lung cancer. Semin Oncol 1989; 16 (Suppl6): 10-21. 14 Bunn PA Jr, Cullen M, Fukuoka M, et al. Chemotherapy in small cell lung cancer: a consensus report. Lung Cancer 1989; 5: 127-34. 15 Cellerino R, Tummarello D, Piga A. Chemotherapy or not in advanced non-small cell lung cancer? Lung Cancer 1990; 6: 99-109. 16 Cerny T, Blair V, Anderson H, et al. Pre treatment prognostic factors and scoring system in 407 small cell lung cancer patients. Int J Cancer 1987; 39: 146-9. 17 Cerny T, Lind MJ, Thatcher N, et al. A simple outpatient treatment with oral ifosfamide and oral etoposide for patients with small cell lung cancer (SCLC). Br J Cancer 1989; 60: 258-61. 18 Cullen M. Evaluating new drugs in patients with chemosensitive tumours: ethical dilemmas in extensive small cell lung cancer. Lung Cancer 1989; 5: 1-7. 19 Cullen MH, Joshi R, Chetiyawardana AD, Woodroffe CM. Mitomycin, ifosfamide and cisplatin in non-small cell lung cancer: treatment good enough to compare. Br J Cancer 1988; 58: 359-61.

N. Thatcher/ Luq 20

21 22 23 24 25

26 21

28

29 30 31

32

33

34 35

36 37

38 39 40 41

Cancer 10 Suppl. 1 (1994) SIl7-S133

s131

de Campos ES, Woll PJ, Steward WP, et al. Clinical and haematological effects of rHu erythropoietin (Epo) during intensive chemotherapy for small cell lung cancer (SCLC). Lung Cancer 1991; 7 (Suppl Abstract 493): 132. De The H., Arriagada R., Thomas F, et al. Major effect on survival of the first course of chemotherapy in limited small cell lung cancer. Lung Cancer 1989; 5: 30. Dodwell DJ. Gurney H, Thatcher N. Dose intensity in cancer chemotherapy. Br J Cancer 1YYO:61: 789-94. Donnadieu N, Paesmans M, Sculier JP. Chemotherapy of non-small cell lung cancer according to disease extent: a meta-analysis of the literature. Lung Cancer 1991; 7: 243-52. Dorward AJ. A prospective study of low dose oral etoposide in poor prognosis small cell lung cancer (SCLC). Lung Cancer 1991; 7 (Suppl Abstract 409): 111. Evans WK. Combination chemotherapy confers modest survival advantage in patients with advanced non-small cell lung cancer: Report of a Canadian Multicenter Randomized Trial. Semin Oncol 1988; 15 (Suppl 7): 42-5. Feld R, Arriagada R, Ball DL, Mattson K, Sorenson JB. Prognostic factors in non-small cell lung cancer: a consensus report. Lung Cancer 1991; 7: 3-5. Frytak S, Shaw E, Eagan R, et al. Accelerated hyperfractionated split-course thoracic radiotherapy (AHSCTRT) and infusion cisplatin based chemotherapy (CT) for small cell lung cancer. Lung Cancer 1991; 7 (Suppl Abstract 586): 157. Gandara DR, Valone FH, Perez EA, Deisseroth AB, Roach M. Rapidly alternating radiotherapy and high dose cisplatin in Stage III non-small cell lung cancer (NSCLC): results of a pilot study. Lung Cancer 1991; 7 (Suppl Abstract 568): 153. Gatzemeier LJ, Hossfeld DK, Neuhauss R, et al. Carboplatin in small cell lung cancer. Semin Oncol 1991; 18 (Suppl 2): 8-16. Gralla RJ. Preoperative and adjuvant chemotherapy in non-small cell lung cancer. Semin Oncol 1988; 15 (Suppl 7): 8-12. Gralla RJ, Kris MG, Martini N, Pisters KMW. Neoadjuvant chemotherapy in non-small cell lung cancer: long term follow up in a 73 patient trial with IIIA staging and clinically apparent mediastinal node involvement. Lung Cancer 1991; 7 (Suppl Abstract 499): 134. Gralla RJ, Zaman MB, Heelan RT, Martini N. Pathological complete responses (pCR) in advanced non-small cell lung cancer (NSCLC) following preoperative chemotherapy. Lung Cancer 1901; 7 (Suppl Abstract 573): 154. Grant SC, Gralla RJ, Kris MG, et al. Phase II trials in small cell lung carcinoma (SCLC) 1970-1990. The case for entering previously treated patients. Lung Cancer 1991; 7 (Suppl Abstract 405): 110. Green MR. Sequential chemotherapy and radiotherapy for initial management of stage IIIA and stage BIB non-small cell lung cancer - induction chemotherapy. Lung Cancer 1991; 7: 77-85. Gurney H, de Campos ES, Dodwell D, et al. Ifosfamide and mitomycin in combination for the treatment of patients with progressive advanced non-small cell lung cancer. Eur J Cancer 1901: 27: 565-8. Hardy JR, Noble T, Smith IE. Symptom relief with moderate dose chemotherapy (mitomycin C, vinblastine and cisplatin) in advanced non-small cell lung cancer. Br J Cancer 1989; 60: 764-6. Henriquez I, Munoz-Galindo L, Rebollo J, et al. Neoadjuvant chemotherapy (NAC) with cisplatin (CDDP), mitomycin-C (MMC) and Vindesine (VDS) in locally advanced non-small cell lung cancer (NSCLC). Proc Am Sot Clin Oncol 1990; 9 (Abstract 876): 227. Hopwood P, Thatcher N. Current studies of quality of life measurement in lung cancer patients. Oncology lYY1; 5: 159-66. Hrubisko M, McGown AT, Prendiville JA, et al. Suitability of cisplatin solutions for 14-day continuous infusion by ambulatory pump. Cancer Chemother Pharmacol 1992; 29: 252-5. Ihde DC. How should we report results of clinical trials on combined chemotherapy and chest irradiation in limited stage small cell lung cancer? Lung Cancer 1989; 5: 23-4. Johnson BE, Salem C, Nesbitt J et al. Limited (LTD) stage small cell lung cancer (SCLC) treated with concurrent BID chest radiotherapy (RT) and etoposide cisplatin (VP/PT) followed by chemotherapy (CT) selected by in vitro drug sensitivity testing (DST). Lung Cancer 1991; 7 (Suppl Abstract 565): 152.

S132

N. Thatcher/Lung Cancer IO Suppl. I (1994) Sl I7-S133

42 Johnson DH, Turrisi AT, Chang AY, Wagner H, Blum R. Alternating chemotherapy (CT’) and thoracic radiotherapy (TRT) in limited small cell lung cancer. Lung Cancer 1991; 7 (Suppl Abstract 576): 155. 43 Klastersky J, Nemec J. Chemotherapy for locally advanced (Stage III) non-small cell lung cancer. Lung Cancer 1991; 7: 105-11. 44 Kris MG, Gralla RJ, Potanovich LM, et al. Assessment of pretreatment symptoms and improvement after EDAM + Mitomycin + Vinblastine (EMV) in patients (pts) with inoperable non-small cell lung cancer (NSCLC). Proc Am Sot Clin Oncol 1990; 9 (Abstract 883): 229. 4.5 Longo DL, Duffey PL, DeVita VT, et al. The calculation of actual or received dose intensity: a comparison of published methods. J Clin Oncol 1991; 9: 2042-51. 46 Maki E, Feld R. Prognostic factors in patients with non-small cell lung cancer. A critique of the world literature. Lung Cancer 1991; 7: 27-34. 47 Osterlind K, Andersen PK. Prognostic factors in patients with small cell lung cancer: multivariate model based on 778 patients treated with chemotherapy with and without irradiation. Cancer Res 1986; 46: 4189-94. 48 Prendiville J, Radford J, Thatcher N, et al. Intensive therapy for small cell lung cancer using carboplatin alternating with cisplatin, ifosfamide, mid-cycle vincristine and radiotherapy. J Clin Oncol 1991; 9: 1446-52. 49 Radford JA, Ryder WDJ, Dodwell D, Anderson H, Thatcher N. Predicting septic complications of chemotherapy. An analysis of 382 patients treated for small cell lung cancer without dose reduction after major sepsis. Eur. J Cancer 1992; 29A: 81-86. 50 Ravasi G, Bedini AV, Milani F, Gramaglia A, et al. Continuous infusion (CI) of cisplatin (CDDP) and concurrent radiotherapy CRT) in non resectable stage III lung cancer. Lung Cancer 1991; 7 (Suppl Abstract 612): 164. 51 Rawson NSB, Peto J. An overview of prognostic factors in small-cell lung cancer: a report from the Subcommittee for the Management of Lung Cancer of the United Kingdom Coordinating Committee on Cancer Research. Br J Cancer 1990; 61: 597-604. 52 Rosti G, Scagliotti G, Crino L, et al. Second cancers as late complications in small cell lung cancer (SCLC) long term survivors. Lung Cancer 1991; 7 (Suppl Abstract 668): 180. 53 Schaake-Koning C, Bogaert W, Dalesio 0, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 1992; 326: 524-30. 54 Shepherd FA, Evans WK, Goss PE, et al. Treatment of small cell lung cancer (SCLC) in the elderly. Lung Cancer 1991; 7 (Suppl Abstract 388): 106. 55 Skarin A, Sheldone T, Malcolm A, et al. Neoadjuvant chemo-radiotherapy of non-small cell lung cancer long-term follow-up. Lung Cancer 1988; 4 (Suppl A166, Abstract 8.2.27). 56 Smit EF, Postmus PE. A phase II study of oral etoposide (OE) 100 mg/day for 21 days (D) Q 5 weeks (W) in untreated elderly (E) and poor performance status (PP.% small cell lung cancer (SCLC) patients (Pts). Lung Cancer 1991; 7 (Suppl Abstract 508): 136. 57 Smith IE, Perren TJ, Ashley SA, et al. Carboplatin, etoposide and ifosfamide as intensive chemotherapy for small cell lung cancer. J Clin Oncol 1990; 8: 899-905. 58 Sorensen JB. How valuable is response as prognostic criterium in non-small cell lung cancer? Lung Cancer 1991; 7: 253-7. 59 Souquet PJ, Fournel P. Doxorubicin, VP 16 and ifosfamide (AVI) with hyperfractionated irradiation of the chest for small cell lung cancer (SCLCJ: Glot 86. Lung Cancer 1991; 7 (Suppl Abstract 607): 163. 60 Splinter TAW. Response rate as criterium to evaluate chemotherapy in non-small cell lung cancer. Lung Cancer 1991; 7: 91-104. 61 Taylor SG, Trybula M, Bonomi PD, et al. Simultaneous cisplatin fluorouracil infusion and radiation followed by surgical resection in regionally localized stage III, non-small cell lung cancer. Ann Thorac Surg 1987; 43: 87-91. 62 Thatcher N, Anderson H, Smith DB, et al. Ifosfamide by bolus as treatment for advanced non-small cell lung cancer. Cancer Chemother Pharmacol 1986; 18 (Suppl2): S30-S34. 63 Thatcher N, Cemy T, Stout R, et al. Ifosfamide, etoposide and thoracic irradiation therapy in 163 patients with urresectable small cell lung cancer. Cancer 1987; 60: 2382-7. 64 Thatcher N, Lind MJ. Carboplatin in small cell lung cancer. Semin Oncol 1990, 17 (Suppl2): 40-8.

N. Thatcher/Lung Cancer 10 Suppl. 1 (1994) S117-S133

s133

65 Thatcher N, Lind M, Stout R, et al. Carboplatin, ifosfamide and etoposide with mid-course vincristine and thoracic radiotherapy for ‘limited’ stage small cell carcinoma of the bronchus. Br J Cancer 1989; 60: 98-101. 66 Thatcher N, Smith DB, Lind MJ, et al. Double alkylating agent therapy with ifosfamide and cyclophosphamide for advanced non-small cell lung cancer. Cancer 1988; 61: 14-18. 67 Tonkin K, Tritchler D, Tannock I. Criteria of tumor response used in clinical trials of chemotherapy. J Clin Oncol 1985; 3: 870-5. 68 Venzon DJ, Phelps R, Edison M et al. Second tumours are the major cause of late mortality in long-term survivors of small-cell lung cancer (SCLC). Lung Cancer 1991; 7 (Suppl Abstract 649): 175. 69 Vincent MD, Ashley SE, Smith IE. Prognostic factors in small cell lung cancer: a simple prognostic index is better than conventional staging, Eur J Cancer 1987; 11: 1589-99. 70 von Rohr A., Anderson H., MC Intosh R, Thatcher N. Phase II study with mitomycin, ifosfamide and carboplatin in inoperable non-small cell lung cancer. Eur J Cancer 1991; 27: 1106-8. 71 Wagner H Jnr, Johnson DH, Turrisi AT. Interdigitated therapy of patients with stage IIIA and BIB non-small cell lung cancer with alternating courses of BID thoracic irradiation (TI) and chemotherapy (CT) with cisplatin-etoposide - results of a pilot study. Lung Cancer 1991; 7 (Suppl Abstract 583): 157. 72 Warr D, McKinney S, Tannock I. Influence of measurement error on assessment of response to anticancer chemotherapy: proposal for new criteria of tumour response. J Clin Oncol 1984; 2: 1040-6. 73 Weiden P, Piantadosi S. Preoperative chemo-radiotherapy in stage III non-small cell lung cancer (NSCLC: A Phase II study of the lung study group (LCSGI. Proc Am Sot Clin Oncol 1988; 7 (Abstract 761): 197. 74 Weitberg A, Posner M, Yashar J, et al. Combined modality therapy for stage IIIA non-small cell carcinoma of the lung (NSCLC). Proc Am Sot Clin Oncol 1990; 9 (Abstract 872): 226. 75 Wolf M, Havemann K, Hans K, et al. Radiotherapy versus chemotherapy followed by radiotherapy in inoperable limited stage non-small cell lung cancer (NSCLC). Lung Cancer 1991; 7 (Suppl Abstract 611): 164.